HOPKINTON, Mass.—Spring Bank Pharmaceuticals Inc., a clinical-stage biopharmaceutical company focused on developing a treatment to functionally cure chronic hepatitis B virus (HBV) infection, announced that early data from a Phase 2 clinical trial demonstrate that even low doses of an orally administered drug candidate, inarigivir, are efficacious in treating a subset of chronically infected patients, HBeAg-negative patients.
Inarigivir, which is designed to have antiviral as well as immunomodulatory activity, could become a major component of a future HBV functional cure, according to Marty Driscoll, Spring Bank’s CEO. Because achieving a functional cure could require a combinatorial approach, Spring Bank is also initiating clinical trials this year combining inarigivir with the currently approved HBV treatment Viread, from California-based Gilead Sciences Inc. “We believe that the treatment paradigm will be our drug given with another compound, eventually enabling patients to stop taking the medicine because they are functionally cured,” Driscoll said.
According to Driscoll, 250,000 to 300,000 people worldwide have the HBV virus, which shuts down the immune response, but only a few of the diagnosed patients get treated in terms of functional care. Inarigivir reignites the immune response and destroys the virus, he explained.
Spring Bank is involved in the discovery and development of a novel class of therapeutics using its proprietary small-molecule nucleic acid hybrid (SMNH) chemistry platform. SMNH compounds are small segments of nucleic acids that the company designs to selectively target and modulate the activity of specific proteins implicated in various disease states. The company’s most advanced SMNH product candidate, inarigivir, is being developed to treat HBV. Other SMNH product candidates are being developed for the treatment of selected cancers through the activation of the stimulator of the interferon genes pathway.
Dr. Nezam Afdhal, chief medical officer of Spring Bank, made an oral presentation at the Asian Pacific Association for the Study of the Liver 2018 Annual Meeting in March to highlight combined results from both the 25 mg and 50 mg cohorts of Part A of the ongoing Phase 2 ACHIEVE trial examining the use of inarigivir for the treatment of chronic HBV. All patients in the two low-dose cohorts have completed sequential dosing of tenofovir disoproxil fumarate marketed by Gilead at 300 mg daily for an additional 12 weeks. Data from the combined first two inarigivir monotherapy cohorts at weeks 12 and 24 demonstrate significant reductions in viral markers, including HBV DNA, HBV RNA and HBsAg, with a favorable safety and tolerability profile.
Data included 30 patients treated with inarigivir and eight placebo patients from the first two low-dose cohorts. The potent antiviral response was seen in eight patients. Additionally, an enhanced antiviral effect was observed in patients with baseline low viral burden. A dose relationship was observed between the pK and antiviral efficacy at these initial low doses of inarigivir. Furthermore, the switch at week 12 to tenofovir disoproxil fumarate 300 mg was associated with a significant reduction in HBV DNA but, as expected, showed little effect on further reductions in HBV RNA, potentially indicating the important dual mechanism of action of inarigivir as a direct-acting antiviral preventing HBV RNA encapsidation and an immuno-modulator stimulating immune-mediated clearance of cccDNA.
“When we examine the 11 HBeAg-negative patients who received inarigivir 25 mg or 50 mg monotherapy, we see a better response rate than in HBeAg-positive patients at the end of 12 weeks treatment. Additionally, nine of the 30 (30 percent) patients had a reduction in HBsAg at either week 12 or week 24 after transitioning to tenofovir disoproxil fumarate, a predictor of HBsAg loss with immune therapies such as interferon, highlighting the potential for inarigivir as a backbone treatment for HBV functional cure,” said Afdhal.
Spring Bank will soon complete the initial 12 weeks of patient dosing for the monotherapy treatment in the third cohort (100 mg) of Part A of Phase 2 ACHIEVE trial. Subject to approval by the Data Safety Monitoring Board, Spring Bank anticipates starting recruitment of the fourth cohort (200 mg) in the first half of 2018.
Additionally, Spring Bank has entered into a clinical trial collaboration with Gilead, under which Gilead is funding and conducting a Phase 2 trial examining the co-administration of inarigivir and tenofovir alafenamide (marketed by Gilead as Vemlidy) in patients with HBV. Similar to the protocol of Part B of the Spring Bank Phase 2 ACHIEVE trial, the protocol for this Phase 2 clinical trial involves 12 weeks concomitant administration of inarigivir (50 mg) and Vemlidy. Following treatment, all patients will receive Vemlidy as a monotherapy for a further 36 weeks. Gilead recently initiated the inarigivir 50 mg + Vemlidy cohort of this clinical trial. Results are expected in the second half of 2018.
“You have to reawaken the immune system to get results in destroying the HBV virus,” Driscoll concluded. “We are hopeful that our candidate ends up in the middle of any treatment regimen.”
DNA immunotherapy shows mettle in chronic HBV infection
PLYMOUTH MEETING, Pa.—In other hepatitis B virus (HBV)-related news recently, Inovio Pharmaceuticals Inc. in March announced that interim Phase 1 results show its DNA immunotherapy designed to treat HBV infection was safe, well-tolerated and generated virus-specific T cells, including CD8+ killer T cells, meeting the objectives of the clinical study.
Preliminary immunology data from the trial revealed that treatment of patients with INO-1800 resulted in the generation of T cells that recognized key components of the hepatitis B virus and reacted by making antiviral cytokines such as interferon-gamma, a protein believed to be linked to clearance of HBV from the liver. INO-1800 was also able to activate and expand CD8+ killer T cells that displayed markers believed to be important for retention in the liver as well as multiple potential mechanisms for killing virally infected cells.
Dr. J. Joseph Kim, Inovio’s president and CEO, said: “Our hepatitis B immunotherapy trial results clearly demonstrate the potential of INO-1800 as immunotherapy for this widespread infection that is a major cause of liver cancer. The key to my optimism is that INO-1800 drove the generation of HBV-specific killer T cells across all cohorts. We see INO-1800 as a key immunotherapy component of effective anti-HBV combination therapy. We have had discussions with several potential partners and expect to further advance this product via collaboration or partnership.”
The secondary endpoints evaluated the cellular and humoral immune response to INO-1800 and investigated the therapy’s effect on several viral and antiviral parameters. All trial subjects, including the ones in the control group, were also medicated with standard-of-care oral antiviral therapies during the study. Inovio plans to report additional data from this trial at upcoming scientific conferences and in a publication.
In a previously published preclinical study, Inovio researchers found the vaccine-specific T cells exhibited a killing function, and could migrate to and stay in the liver and cause clearance of target cells without evidence of liver injury. This animal study was the first study to provide evidence that intramuscular immunization can induce killer T cells that can migrate to the liver and eliminate target cells, demonstrating the potential of this immunotherapy.